Skeletal diseases such as arthritis, osteoporosis and bone tumours affect millions of people worldwide. Researchers hope to use regenerative medicine to repair the damage caused by these diseases in the future. One of our research focuses is on the genetic regulation of skeletal development in zebrafish. Although zebrafish are a small tropical fish, we now know that the skeleton develops in much the same way as in humans. We hope that by understanding how the skeleton is generated in zebrafish, we will provide information on how to regenerate the skeleton in human patients.

One disease which our research has already shed light on is called Hereditary Multiple Exostoses. Hereditary Multiple Exostoses causes the formation of benign bone tumours in children. Besides causing severe skeletal deformity, the bone tumours can compress nerves or other tissue resulting in chronic pain. Although the tumours can usually be surgically removed, they sometimes recur, or are in positions that prevent surgery. We have identified two strains of zebrafish whose offspring have skeletal defects that resemble those of patients with Hereditary Multiple Exostoses.

We have found that each strain carries a mutated form of an essential gene. Importantly, these two genes are also found in humans and thus by analysing their function in zebrafish we may shed light on their role in humans. Our study has elucidated the roles of these genes during normal skeletal development and has allowed us to generate a model for how genetic changes give rise to bone tumours in humans.

Technical Summary

Our research focuses on the role of intercellular signalling pathways during musculoskeletal skeletal development in zebrafish. We have three projects ongoing in our group:

1 - What is the role of heparin sulphate proteoglycans (HSPGs) during skeletogenesis? Although HSPGs are ubiquitous structural components of the extracellular matrix, they are also thought to play very specific roles in cell-cell signalling during development. We found that two zebrafish lines carry mutations in ext2 and papst1, two genes that are essential for the synthesis of HSPGs. Using these lines we have shown that HSPGs are not required for chondrocyte differentiation, but are required during cartilage morphogenesis and hypertrophy. We have also found that osteoblast differentiation requires HSPGs. Our results help to shed light on the aetiology of a disease called multiple osteochondromas which is caused by mutations in human ext2.

2 - How do developmental signalling pathways regulate osteoblast differentiation? Osteoblasts in zebrafish follow the same differentiation pathway as in mammals: The runx2 genes are expressed in early skeletal precursors, followed by osterix and then finally by genes encoding bone proteins such as osteonectin and collagen1. We have begun to analyse how different signalling pathways regulate these steps during osteoblastogenesis using heatshock induction of signalling pathway components and pharmaceuticals that target individual pathways.

3 - Which signalling pathways regulate skeletal muscle development? Very little is known about how individual muscles know where to attach to the skeleton. We have been analysing a set of mutants that affect specific muscles while leaving other muscles and the underlying skeleton unaffected. This analysis promises to elucidate how muscular and skeletal development are coordinated.